A Phase Ib, Dose-Escalation Study of Augmented Lymphodepletion and CAR T-cell Priming With Low-dose Total Body Irradiation in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphomas and Multiple Myeloma Receiving Treatment With Commercial CD19 or BCMA-directed CAR T-cell Therapies
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Incidence of Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This is a clinical trial to evaluate the safety of combining CAR T-cell therapy with low-dose total body irradiation (LD-TBI) in patients with previously treated large B-cell lymphoma (LBCL) or multiple myeloma (MM). The investigators' hypothesis is that the combination will make the immune system more active in fighting cancer by increasing the display of antigens and activating pathways that lead to cell death, including death receptors like FAS and TRAIL2. This approach is expected to help the CAR T cells grow and last longer, leading to stronger anti-tumor effects and more cancer cell deaths. Participants will receive LDTBI treatment before their CAR T cell therapy and will be followed up for 2 years.
详细描述
This is a single-center, open-label, non-randomized, Phase Ib trial evaluating dose escalation of low-dose total body irradiation (LD-TBI) combined with standard-of-care CAR T-cell therapy in patients with relapsed or refractory large B-cell lymphoma (LBCL) or multiple myeloma (MM). The study includes two disease-specific cohorts: Cohort 1 (LBCL) receives commercial CD19-directed CAR T-cell therapy (axicabtagene ciloleucel or lisocabtagene maraleucel), and Cohort 2 (MM) receives commercial BCMA-directed CAR T-cell therapy (ciltacabtagene autoleucel). In CAR T-cell therapy, T-cells are removed via apheresis, modified to target the tumor, and infused back into the patient after lymphodepleting chemotherapy. On the same day as CAR T-cell infusion, prior to infusion, patients receive a single dose of LD-TBI.
Each cohort follows a standard 3+3 dose-escalation design (Part 1) to identify the maximum tolerated dose (MTD) across three planned dose levels (0.5 Gy, 1.0 Gy starting dose, and 2.0 Gy), based on dose-limiting toxicities occurring within 28 days of treatment. Once the MTD is identified, an expansion cohort (Part 2) of up to 10 additional participants per cohort will be randomized 1:1 to the MTD or a dose level below it to further evaluate safety and activity. Approximately 16-22 participants are anticipated per disease cohort. Participants will be followed for up to 2 years after treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •For Diffuse Large B-Cell Lymphoma (DLBCL) Cohort:
- •Diagnosis of DLBCL that is refractory to first-line chemoimmunotherapy, relapses within 12 months of first-line chemoimmunotherapy, relapses after 12 months in a transplant-ineligible patient, or is relapsed/refractory after two or more lines of systemic therapy. Eligible histologies include DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from indolent lymphoma (follicular lymphoma, marginal zone lymphoma, or chronic lymphocytic leukemia)
- •Age ≥18 years
- •ECOG performance status ≤2
- •Measurable disease on PET/CT or CT per Lugano Criteria
- •Adequate organ function: ANC ≥1000 cells/mm³; platelet count ≥75,000 cells/mm³; creatinine clearance or eGFR ≥45 mL/min; total bilirubin ≤2.0x ULN; AST or ALT ≤3.0x ULN; left ventricular ejection fraction >40%
- •For Multiple Myeloma (MM) Cohort:
- •Relapsed or refractory multiple myeloma after ≥1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, with disease refractory to lenalidomide (progression within 60 days of last lenalidomide dose)
- •Age ≥18 years
- •ECOG performance status ≤2
- •Adequate organ function: ANC ≥1000 cells/mm³; platelet count ≥75,000 cells/mm³; creatinine clearance or eGFR ≥30 mL/min; total bilirubin ≤2.0x ULN; AST or ALT ≤3.0x ULN; left ventricular ejection fraction >40%
排除标准
- •For DLBCL Cohort:
- •History of previous total body irradiation
- •Prior CAR T-cell therapy
- •Clonal cytopenia of uncertain significance (CCUS)
- •Prior history of myeloid malignancies (MDS/AML or MPN), T-cell lymphoblastic lymphoma/leukemia, or B-cell acute lymphoblastic leukemia
- •Current or prior CNS involvement by lymphoma
- •Significant cardiovascular impairment (CHF greater than NYHA Class II, uncontrolled hypertension, unstable angina, MI or stroke within 6 months, or cardiac ventricular arrhythmia)
- •Decompensated cirrhosis
- •Active HIV, hepatitis B, or hepatitis C infection
- •Active uncontrolled systemic fungal, bacterial, or viral infection
- •Pregnancy
- •For MM Cohort:
- •History of previous total body irradiation
- •History of myelodysplastic syndrome, CCUS, or concurrent active hematological malignancy with bone marrow involvement
- •Active HIV, hepatitis B, or hepatitis C infection
- •Active uncontrolled systemic fungal, bacterial, or viral infection
- •Prior CAR T-cell therapy
- •Active or history of CNS myeloma or leptomeningeal infiltration
- •Pregnancy
结局指标
主要结局
Incidence of Dose-Limiting Toxicities (DLTs)
时间窗: Through Day 28 post-CAR T cell infusion
This outcome measures the number of participants experiencing a dose-limiting toxicity (DLT) at each LD-TBI dose level, within 28 days following CAR T-cell infusion. This measure is used to assess the safety and tolerability of the treatment regimen across escalating radiation dose levels and to determine the maximum tolerated dose (MTD).
次要结局
- Incidence and Severity of Cytokine Release Syndrome (CRS)(12 months post-LDTBI and CAR T cell therapy combination)
- Incidence and Severity of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)(12 months post-LDTBI and CAR T cell therapy combination)
- Incidence and Severity of Immune Effector Cell-Associated Hemophagocytic Syndrome (IEC-HS)(12 months post-LDTBI and CAR T cell therapy combination)
- Incidence of Delayed Immune Effector Cell-Associated Hematotoxicity (ICAHT)(12 months post-LDTBI and CAR T cell therapy combination)
- Incidence and Severity of Treatment-Related Adverse Events(From Lymphodepletion (Day -5) through Day 360)
- Overall Response Rate (ORR)(At Days +30, +90, +180, and +365 post-CAR T-cell infusion)
- Overall Survival (OS)(12 months post-LDTBI and CAR T cell therapy combination)
- Progression-Free Survival (PFS)(12 months post-LDTBI and CAR T cell therapy combination)
- Duration of Response (DoR)(Assessed throughout study follow-up (up to 2 years))
- Adverse Event of Interest(From CAR T-cell infusion (Day 0) through Day 360)